Human bones are subject to a continuous dynamic process of reconstruction which involves bone reabsorption and bone synthesis. These processes are controlled by cell types which are specialised for this purpose. Bone synthesis is based on the deposition of bone matrix by osteoblasts, while bone reabsorption is based on the breakdown of bone matrix by osteoclasts. The majority of bone diseases are due to the balance between bone formation and bone reabsorption being disturbed. Osteoporosis is characterised by a loss of bone matrix. Activated osteoclasts are multinuclear cells, having a diameter of up to 400 xcexcm which demolish bone matrix. Activated osteoclasts attach themselves to the surface of the bone matrix and secrete proteolytic enzymes and acids into the so-called sealing zone, the region between their cell membrane and the bone matrix. The acid environment and the proteases bring about the breakdown of the bone.
Studies have demonstrated that the attachment of osteoclasts to the bones is regulated by integrin receptors on the cell surface of osteoclasts.
Integrins are a superfamily of receptors which includes, inter alia, the fibrinogen receptor xcex1IIbxcex23 on the blood platelets and the vitronectin receptor xcex1Vxcex23. The vitronectin receptor, xcex1Vxcex23, is a membrane glycoprotein which is expressed on the cell surface of a number of cells such as endothelial cells, cells of the smooth blood vessel musculature, osteoclasts and tumor cells. The xcex1Vxcex23 vitronectin receptor which is expressed on the osteoclast membrane regulates the process of attachment to the bones and of bone reabsorption and consequently contributes to osteoporosis.
In this context, xcex1Vxcex23 binds to bone matrix proteins, such as osteopontin, bone sialoprotein and thrombospondin, which contain the tripeptide motif Arg-Gly-Asp (or RGD).
Horton and coworkers describe RGD peptides and an anti-vitronectin receptor antibody (23C6) which inhibit tooth breakdown by osteociasts and the migration of osteoclasts (Horton et al., Exp. Cell. Res. 1991, 195, 368). In J. Cell Biol. 1990, 111, 1713, Sato et al. report that echistatin, an RGD peptide from snake venom, is a potent inhibitor of bone reabsorption in a tissue culture and an inhibitor of the attachment of osteoclasts to bones. Fischer et al. (Endocrinology, 1993, 132, 1411) were able to demonstrate that, in the rat, echistatin also inhibits bone reabsorption in vivo.
The xcex1Vxcex23 vitronectin receptor on human cells of the smooth blood vessel musculature of the aorta stimulates migration of these cells into the neointima, a process which finally leads to arteriosclerosis and restenosis following angioplasty (Brown et al., Cardiovascular Res. 1994, 28, 1815).
Brooks et al. (Cell 1994, 79, 1157) have demonstrated that antibodies against xcex1Vxcex23 or xcex1Vxcex23 antagonists are able to shrink tumors by inducing the apoptosis of blood vessel cells during angiogenesis. Chersh et al. (Science 1995, 270, 1500) describe anti-xcex1Vxcex23 antibodies or xcex1Vxcex23 antagonists which inhibit bFGF-induced angiogenesis processes in the rat eye, something which might be of therapeutic value in the treatment of retinopathies.
EP-A 449 079, EP-A 530 505, EP-A 566 919 and WO 93/18057 describe hydantoin derivatives, and WO 95/14008 describes substituted 5-membered ring heterocycles, both of which sets of compounds exhibit thrombocyte aggregation-inhibiting effects. Patent Application WO 94/12181 describes substituted aromatic or non-aromatic ring systems, and WO 94/08577 describes substituted heterocycles, both of which sets of compounds act as fibrinogen receptor antagonists and inhibitors of platelet aggregation. EP-A-528 586 and EP-A-528 587 disclose aminoalkyl-substituted or heterocyclyl-substituted phenylalanine derivatives, and WO 95/32710 describes aryl derivatives, all of which sets of compounds act as inhibitors of bone reabsorption by osteoclasts. WO 95/28426 describes RGD peptides which act as inhibitors of bone reabsorption, angiogenesis and restenosis. WO 96/00574 describes benzodiazepines, and WO 96/00730 describes fibrinogen receptor antagonist templates, in particular benzodiazepines which are linked to a 5-membered ring carrying a nitrogen, both of which sets of compounds act as vitronectin receptor antagonists.
It is therefore an object of the instant invention to provide the compounds of formula I. It is a further object to provide pharmaceutical compositions of the compounds of formula I, and methods of treating with these compositions diseases associated with vitronectin receptor binding. It is a further object to provide methods for preparing the compounds of formula I. It is a further object to provide an in vitro method of inhibiting the activation of vitronectin receptor using the compounds of formula I.
The present invention relates to compounds of the formula I and their physiologically tolerated salts, to pharmaceutical preparations comprising these compounds and to their preparation and use as medicaments, in particular as inhibitors of bone reabsorption by osteoclasts, as inhibitors of tumor growth and tumor metastasis, as inflammation inhibitors, for the treatment or prophylaxis of cardiovascular diseases such as arteriosclerosis or restenosis, for the treatment or prophylaxis of nephropathies and retinopathies, for example diabetic retinopathy, and also as vitronectin receptor antagonists for the treatment and prophylaxis of diseases which are based on the interaction between vitronectin receptors and their ligands in cellxe2x80x94cell or cell-matrix interaction processes. The invention furthermore relates to the use of the compounds of the formula I, and their physiologically tolerated salts and pharmaceutical preparations comprising these compounds, as medicaments for alleviating or curing diseases which are associated, at least in part, with an undesirable degree of bone reabsorption, angiogenesis or proliferation of cells of the smooth blood vessel musculature.
The novel compounds of the formula I inhibit bone reabsorption by osteoclasts. Bone diseases against which the novel compounds can be employed are, in particular, osteoporosis, hypercalcemia, osteopenia, e.g. elicited by metastases, dental diseases, hyperparathyroidism, periarticular erosions in rheumatoid arthritis and Paget""s disease.
In addition, the compounds of the formula I can be employed for the alleviation, avoidance or therapy of bone diseases which are provoked by glucocorticoid therapy, steroid therapy or corticosteroid therapy, or by a lack of sexual hormone(s). All these diseases are characterized by bone loss which is due to the imbalance between bone synthesis and bone breakdown.
Moreover, the compounds of formula I can be used as carrier of agents which are effective in the treatment of the afore-mentioned diseases thus allowing the specific transfer of said agents to the desired target (=Drug Targeting, see e.g. Targeted Drug Delivery, R. C. Juliano, Handbook of Experimental Pharmacology, Vol. 100, Ed. Born, G. V. R. et al, Springer Verlag), herein incorporated by reference.
The present invention relates to 5-membered ring heterocycles of the formula I, 
in which:
W is R1xe2x80x94Axe2x80x94Bxe2x80x94Dxe2x80x94C(R16), R1xe2x80x94Axe2x80x94Bxe2x80x94Dxe2x80x94C(R16)xe2x95x90C, 
xe2x80x83or 
xe2x80x83with it being possible for the ring systems 
xe2x80x83to contain 1 or 2 heteroatoms from the group N, O and S, to be saturated or unsaturated, once or more than once, and be substituted by 1-3 substituents from R16 or substituted, once or twice, by doubly bonded O or S;
Y is Cxe2x95x90O, Cxe2x95x90S or xe2x80x94CH2xe2x80x94;
Z is N(RO), O, S or xe2x80x94CH2xe2x80x94;
A is a direct linkage, (C1-C8)-alkanediyl, xe2x80x94NR2xe2x80x94Nxe2x95x90CR2xe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94C(O)Oxe2x80x94, xe2x80x94NR2xe2x80x94C(O)Sxe2x80x94, xe2x80x94NR2xe2x80x94C(S)xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94C(S)xe2x80x94Oxe2x80x94, xe2x80x94NR2xe2x80x94C(S)xe2x80x94Sxe2x80x94, xe2x80x94NR2xe2x80x94S(O)nxe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94S(O)nxe2x80x94Oxe2x80x94, xe2x80x94NR2xe2x80x94S(O)nxe2x80x94, (C3-C12)-cycloalkanediyl, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94(C5-C14)-arylene-C(O)xe2x80x94NR2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, (C5-C14)-arylene-, xe2x80x94COxe2x80x94, (C5-C14)-arylene-COxe2x80x94, xe2x80x94NR2xe2x80x94, xe2x80x94SO2xe2x80x94NR2, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94Nxe2x95x90CR2xe2x80x94, xe2x80x94R2Cxe2x95x90Nxe2x80x94, xe2x80x94CR2xe2x95x90CR3xe2x80x94 or xe2x80x94(C5-C14)-arylene-S(O)nxe2x80x94, which in each case can be substituted by NR2 and/or substituted, once or twice, by (C1-C8)-alkanediyl, such as xe2x80x94(C1-C8)-alkanediyl-COxe2x80x94NR2xe2x80x94(C1-C8)-alkanediyl, xe2x80x94(C1-C8)-alkanediyl-COxe2x80x94NR2xe2x80x94 or xe2x80x94COxe2x80x94NR2xe2x80x94(C1-C8)-alkanediyl;
B is a direct linkage, (C1-C8)-alkanediyl, (C5-C10)-arylene, (C3-C8)-cycloalkanediyl, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94NR2xe2x80x94, xe2x80x94C(O)xe2x80x94, NR2xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2, xe2x80x94NR2xe2x80x94C(S)xe2x80x94NR2xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)xe2x80x94NR2xe2x80x94, xe2x80x94S(O)2xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94S(O)xe2x80x94, xe2x80x94NR2xe2x80x94S(O)2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94CR2xe2x95x90CR3xe2x80x94, which in each case can be substituted once or twice by (C1-C6)-alkanediyl, such as 
xe2x80x83or xe2x80x94(CH2)2xe2x80x94NR2xe2x80x94C(O)xe2x80x94; or is a divalent radical of a 5- or 6-membered saturated or unsaturated ring which contains 1 or 2 nitrogen atoms and can be substituted, once or twice, by (C1-C6)-alkyl or doubly bonded oxygen or sulfur;
D is a direct linkage, (C1-C8)-alkanediyl, (C5-C10)-arylene, xe2x80x94Oxe2x80x94, xe2x80x94NR2xe2x80x94, xe2x80x94COxe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94COxe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94C(S)xe2x80x94NR2xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CSxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)2xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94S(O)xe2x80x94, xe2x80x94NR2xe2x80x94S(O)2xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CR2xe2x95x90CR3xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94NR2xe2x80x94Nxe2x95x90CR2xe2x80x94, xe2x80x94Nxe2x95x90CR2, xe2x80x94R2Cxe2x95x90Nxe2x80x94 or xe2x80x94CH(OH)xe2x80x94, which in each case can be substituted, once or twice, by (C1-C8)-alkanediyl, xe2x80x94CR2xe2x95x90CR3xe2x80x94 or (C5-C6)-arylene, such as 
xe2x80x83-phenylene-NR2xe2x80x94C(O)xe2x80x94 or xe2x80x94(CH2)2xe2x80x94S(O)2xe2x80x94CH2xe2x80x94
E is a direct linkage, (C1-C6)-alkanediyl, (C2-C6)-alkenediyl, (C2-C6)-alkynediyl, phenylene, phenylene-(C1-C3)-alkanediyl or (C1-C3)-alkanediylphenylene;
F is defined as D;
G is 
L is C(R16) or N;
R0 is H, (C1-C8)-alkyl which is optionally substituted, once or more than once, by fluorine, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, (C5-C14)-aryl, (C5-C14)-aryl-(C1-C8)-alkyl, (C1-C8)-alkyl-C(O)xe2x80x94, (C3-C12)-cycloalkyl-C(O), (C3-C12)-cycloalkyl-(C1-C6)-alkyl-C(O), (C5-C14)-aryl-C(O)xe2x80x94 or (C5-C14)-aryl-(C1-C6)-alkyl-C(O), with it being possible for the alkyl radicals to be substituted, once or more than once, by fluorine;
R1 is R2xe2x80x94C(xe2x95x90NR2)NR2xe2x80x94, R2R3Nxe2x80x94C(xe2x95x90NR2)xe2x80x94, R2R3Nxe2x80x94Cxe2x80x94(xe2x95x90NR2)xe2x80x94NR2, or a 4- or 14-membered, monocyclic or polycyclic, aromatic or non-aromatic ring system which can optionally contain 1-4 heteroatoms from the group N, O and S and can optionally be substituted, once or more than once, by substituents from the group R12, R13, R14 and R15;
R2 and R3 are, independently of each other, H, (C1-C10)-alkyl, which is optionally substituted, once or more than once, by fluorine, (C3-C12)-cycloalkyl, (C3 -C12)-cycloalkyl-(C1-C8)-alkyl, (C5-C14)-aryl, (C5-C14)-aryl-(C1-C8)-alkyl, H2N, R8ONR9, R8OR9, R8OC(O)R9, R8xe2x80x94(C5-C14)-aryl-R9, R8R8NR9, HOxe2x80x94(C1-C8)-alkyl-NR8R9, R8R8NC(O)R9, R8C(O)NR8R9, R8C(O)R9, R8R8Nxe2x80x94C(xe2x95x90NR8)xe2x80x94, R8R8Nxe2x80x94C(xe2x95x90NR8)xe2x80x94NR8xe2x80x94 or (C1-C18)-alkylcarbonyloxy-(C1-C6)-alkoxycarbonyl;
R4, R5, R6 and R7 are, independently of each other, H, fluorine, OH, (C1-C8)-alkyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, or R8OR9, R8SR9, R8CO2R9, R8OC(O)R9, R8xe2x80x94(C5-C14)-aryl-R9, R8N(R2)R9, R8R8NR9, R8N(R2)C(O)OR9, R8S(O)nN(R2)R9, R8OC(O)N(R2)R9, R8C(O)N(R2)R9, R8N(R2)C(O)N(R2)R9, R8N(R2)S(O)nN(R2)R9, R8S(O)nR9, R8SC(O)N(R2)R9, R8C(O)R9, R8N(R2)C(O)R9 or R8N(R2)S(O)nR9;
R8 is H, (C1-C8)-alkyl, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, (C5-C14)-aryl or (C5-C14)-aryl-(C1-C8)-alkyl, with it being possible for the alkyl radicals to be substituted, once or more than once, by fluorine;
R9 is a direct linkage or (C1-C8)-alkanediyl;
R10 is C(O)R11, C(S)R11, S(O)nR11, P(O)nR11 or a four- to eight-membered, saturated or unsaturated heterocycle which contains 1, 2, 3 or 4 heteroatoms from the group N, O and S, such as tetrazolyl, imidazolyl, pyrazolyl, oxazolyl or thiadiazolyl;
R11 is OH, (C1-C8)-alkoxy, (C5-C14)-aryl-(C1-C8)-alkoxy, (C5-C14)-aryloxy, (C1 -C8)-alkylcarbonyloxy-(C1-C4)-alkoxy, (C5-C14)-aryl-(C1-C8)-alkylcarbonyloxy-(C1-C6)-alkoxy, NH2, mono- or di-(C1-C8-alkyl)-amino, (C5-C14)-aryl-(C1-C8)-alkylamino, (C1-C8)-dialkylaminocarbonylmethyloxy, (C5-C14)-aryl-(C1-C8)-dialkylaminocarbonylmethyloxy or (C5-C14)-arylamino or a L- or D-amino acid;
R12, R13, R14 and R15 are, independently of each other, H, (C1-C10)-alkyl which is optionally substituted, once or more than once, by fluorine, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, (C5-C14)-aryl, (C5-C14)-aryl-(C1-C8)-alkyl, H2N, R8ONR9, R8OR9, R8OC(O)R9, R8R8NR9, R8xe2x80x94(C5-C14)-aryl-R9, HOxe2x80x94(C1-C8)-alkyl-N(R2)R9, R8N(R2)C(O)R9, R8C(O)N(R2)R9, R8C(O)R9, R2R3Nxe2x80x94C(xe2x95x90NR2)xe2x80x94NR2xe2x80x94, R2R3Nxe2x80x94C(xe2x95x90NR2), xe2x95x90O or xe2x95x90S; with it being possible for two adjacent substituents from R12 to R15 also together being xe2x80x94OCH2Oxe2x80x94, xe2x80x94OCH2CH2Oxe2x80x94 or xe2x80x94OC(CH3)2Oxe2x80x94;
R16 is H, (C1-C10)-alkyl which is optionally substituted, once or more than once, by fluorine, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, (C5-C14)-aryl, (C5-C14)-aryl-(C1-C8)-alkyl, (C2-C20)-alkenyl or (C2-C10)-alkynyl;
m is 1, 2, 3, 4, 5 or 6;
n is 1 or 2;
p and q are, independently of each other, 0 or 1;
and the physiologically tolerated salts thereof,
with compounds being excepted in which R1xe2x80x94Axe2x80x94Bxe2x80x94Dxe2x80x94C(R16) or R1xe2x80x94Axe2x80x94Bxe2x80x94Dxe2x80x94C(R16)xe2x95x90C is R1xe2x80x94Kxe2x80x94C(R16) or R1xe2x80x94Kxe2x80x94CHxe2x95x90C (R16xe2x95x90H), where, in this case,
R1 is Xxe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94(CH2)p, X1xe2x80x94NHxe2x80x94(CH2)p or 4-imidazolyl-CH2xe2x80x94, with it being possible for p to be an integer from 0 to 3,
X is hydrogen, (C1-C6)-alkyl, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, (C1-C18)-alkylcarbonyloxy-(C1-C6)-alkoxycarbonyl, (C6-C14)-arylcarbonyl, (C6-C14)-aryloxycarbonyl, (C6-C14)-aryl-(C1-C6)-alkoxycarbonyl, hydroxyl, (C1-C6)-alkoxy, (C6-C14)-Aryl-(C1-C6)-alkoxy or amino, with the aryl groups in X being pure carbocycles which are optionally substituted once or more than once,
X1 is (C4-C14)-arylcarbonyl, (C4-C14)-aryloxycarbonyl, (C4-C14)-aryl-(C1-C6)-alkoxycarbonyl, (C4-C14)-aryl-(C1-C6)-alkoxy or Rxe2x80x2xe2x80x94NHxe2x80x94C(xe2x95x90Nxe2x80x94Rxe2x80x3), where Rxe2x80x2 and Rxe2x80x3 have, independently of each other, the meanings of X and where the aryl groups in X1 are pure carbocycles which are optionally substituted once or more than once and
K is (C1-C6)-alkanediyl, (C3-C7)-cycloalkanediyl, phenylene, phenylene-(C1 -C6)-alkanediyl, (C1-C6)-alkanediyl-phenylene, phenylene-(C2-C6)-alkenediyl or a divalent radical of a 5- or 6-membered, saturated or unsaturated ring which contains 1 or 2 nitrogen atoms and can be substituted, once or twice, by (C1-C6)-alkyl or doubly bonded oxygen or sulfur.
The alkyl radicals which appear in the substituents can be straight-chain or branched, saturated or unsaturated once or more than once. The same applies in a corresponding manner to radicals which are derived therefrom, such as alkoxy. Cycloalkyl radicals can be monocyclic, bicyclic or tricyclic.
Monocyclic cycloalkyl radicals are, in particular, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl which, however, can also be substituted, for example by (C1-C4)-alkyl. Examples of substituted cycloalkyl radicals which may be mentioned are 4-methylcyclohexyl and 2,3-dimethylcyclopentyl.
Bicyclic and tricyclic cycloalkyl radicals can be unsubstituted or be substituted in any suitable positions by one or more oxo groups and/or one or more identical or different (C1-C4)-alkyl groups, for example methyl groups or isopropyl groups, preferably methyl groups. The free bond of the bicyclic or tricyclic radical can be located in any position in the molecule; the radical can consequently be bonded by way of a bridgehead atom or an atom in a bridge. The free bond can also be located in any stereochemical position, for example in an exo position or an endo position.
Examples of parent compounds of bicyclic ring systems are norbornane (=bicyclo[2.2.1]heptane), bicyclo[2.2.2]octane and bicyclo[3.2.1]octane. An example of a system which is substituted by an oxo group is camphor (=1,7,7-trimethyl-2-oxobicyclo[2.2.1]heptane).
Examples of parent compounds of tricyclic systems are twistane (=tricyclo[4.4.0.03,8]decane, adamantane (=tricyclo[3.3.1.13,7]decane), noradamantane (=tricyclo[3.3.1.03,7]nonane), tricyclo[2.2.1.02,6]heptane, tricyclo[5.3.2.04,9]dodecane, tricyclo[5.4.0.02,9]undecane or tricyclo[5.5.1.03,11]tridecane.
Examples of aryl are phenyl, naphthyl, biphenylyl, anthryl or fluorenyl, with 1-naphthyl, 2-naphthyl and in particular, phenyl being preferred. Aryl radicals, in particular phenyl radicals, can be substituted, once or more than once, preferably once, twice or three times, by identical or different radicals from the group (C1-C8)-alkyl, in particular (C1-C4)-alkyl, (C1-C8)-alkoxy, in particular (C1-C4)-alkoxy, halogen, such as fluorine, chlorine and bromine, nitro, amino, trifluoromethyl, hydroxyl, methylenedioxy, ethylenedioxy, xe2x80x94OC(CH3)2Oxe2x80x94, cyano, hydroxycarbonyl, aminocarbonyl, (C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyloxy, (R17O)2P(O), (R17O)2P(O)xe2x80x94Oxe2x80x94, in which R17xe2x95x90H, (C1-C18)-alkyl, (C6-C14)-aryl or (C6-C14)-aryl-(C1-C8)-alkyl or tetrazolyl.
In monosubstituted phenyl radicals, the substituent can be located in the 2, the 3 or the 4 position, with the 3 and the 4 positions being preferred. If phenyl is substituted twice, the substituents can be in the 1, 2 position, 1, 3 position or 1, 4 position relative to each other. Preferably, in phenyl radicals which are substituted twice, the two substituents are arranged in the 3 and the 4 position, based on the linkage site.
Aryl groups can also be monocyclic or polycyclic aromatic ring systems in which from 1 to 5 carbon atoms can be replaced by from 1 to 5 heteroatoms, such as 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, isoindolyl, indazolyl, phthalazinyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolinyl, xcex2-carbolinyl, or a benzofused, cyclopenta-fused, cyclohexa-fused or cyclohepta-fused derivative of these radicals. These heterocycles can be substituted by the same substituents as the abovementioned carbocyclic aryl systems.
Within this series of aryl groups, those which are preferred are monocyclic or bicyclic aromatic ring systems having 1-3 heteroatoms from the group N, O and S which can be substituted by 1-3 substituents from the group (C1-C6)-alkyl, (C1-C6)-alkoxy, fluorine, Cl, NO2, NH2, trifluoromethyl, OH, (C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyloxy or benzyl.
In this context, those aryl groups which are particularly preferred are monocyclic or bicyclic aromatic 5-10 membered ring systems having 1-3 heteroatoms from the group N, O and S which can be substituted by 1-2 substituents from the group (C1-C4)-alkyl, (C1-C4)-alkoxy, phenyl, phenoxy, benzyl or benzyloxy.
The afore-mentioned applies in a corresponding manner to divalent radicals which are derived from alkyl, cycloalkyl and aryl such as alkanediyl, alkenediyl, alkynediyl, cycloalkanediyl and arylene.
Compounds of the formula I are also preferred which carry a lipophilic radical R4, R5, R6 or R7, such as benzyloxycarbonylamino, cyclohexylmethylcarbonylamino, etc.
Compounds of the formula I are furthermore preferred in which R1 is a 4-14-membered, monocyclic or polycyclic, aromatic or non-aromatic ring system which can optionally contain 1-4 heteroatoms from the group N, O and S and can optionally be substituted, once or more than once, by substituents from the group R12, R13, R14 and R15, such as 
Yxe2x80x2 being NR2, O or S.
L- or D-amino acids can be natural or unnatural amino acids. xcex1-Amino acids are preferred. Those which may be mentioned by way of example are (cf. Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Volume XV/1 and 2, Georg Thieme Verlag, Stuttgart, 1974):
Aad, Abu, xcex3Abu, ABz, 2ABz, xcex5Aca, Ach, Acp, Adpd, Ahb, Aib, xcex2Aib, Ala, xcex2Ala, xcex94Ala, Alg, AlI, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bph, Can, Cit, Cys, (Cys)2, Cyta, Daad, Dab, Dadd, Dap, Dapm, Dasu, Djen, Dpa, Dtc, Fel, Gin, Glu, Gly, Guv, hAla, hArg, hCys, hGln, hGlu, His, hlIe, hLeu, hLys, hMet, hPhe, hPro, hSer, hThr, hTrp, hTyr, Hyl, Hyp, 3Hyp, Ile, Ise, Iva, Kyn, Lant, Lcn, Leu, Lsg, Lys, xcex2Lys, xcex94Lys, Met, Mim, Min, nArg, NIe, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg, Pic, Pro, xcex94Pro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi, xcex2Thi, Thr, Thy, Thx, Tia, Tle, Tly, Trp, Trta, Tyr, Val, tert-butylglycine (Tbg), neopentylglycine (Npg), cyclohexylglycine (Chg), cyclohexylalanine (Cha), 2-thienylalanine (Thia), 2,2-diphenylaminoacetic acid, 2-(p-tolyl)-2-phenylaminoacetic acid and 2-(p-chlorophenyl)aminoacetic acid;
and, in addition:
pyrrolidine-2-carboxylic acid; piperidine-2-carboxylic acid; 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; decahydroisoquinoline-3-carboxylic acid; octahydroindole-2-carboxylic acid; decahydroquinoline-2-carboxylic acid; octahydrocyclopenta[b]pyrrole-2-carboxylic acid; 2-azabicyclo[2.2.2]octane-3-carboxylic acid; 2-azabicycio[2.2.1]-heptane-3-carboxylic acid; 2-azabicyclo[3.1.0]hexane-3-carboxylic acid; 2-azaspiro[4.4]nonane-3-carboxylic acid; 2-azaspiro[4.5]decane-3-carboxylic acid; spiro(bicyclo[2.2.1]heptane)-2,3-pyrrolidine-5-carboxylic acid; spiro(bicyclo[2.2.2]octane)-2,3-pyrrolidine-5-carboxylic acid; 2-azatricyclo[4.3.0.16,9]decane-3-carboxylic acid; decahydrocyclo-hepta[b]pyrrole-2-carboxylic acid; decahydrocycloocta[c]pyrrole-2-carboxylic acid; octahydrocyclopenta[c]pyrrole-2-carboxylic acid; octahydroisoindole-1-carboxylic acid; 2,3,3a,4,6a-hexahydrocyclopenta[b]pyrrole-2-carboxylic acid; 2,3,3a,4,5,7a-hexahydroindole-2-carboxylic acid; tetrahydrothiazole-4-carboxylic acid; isoxazolidine-3-carboxylic acid; pyrazolidine-3-carboxylic acid and hydroxypyrrolidine-2-carboxylic acid, which can all optionally be substituted (see the following formulae): 
The heterocycles underlying the abovementioned radicals are disclosed, for example, in U.S. Pat. Nos. 4,344,949; 4,374,847; 4,350,704; EP-A 29,488; EP-A 31,741; EP-A 46,953; EP-A 49,605; EP-A 49,658; EP-A 50,800; EP-A 51,020; EP-A 52,870; EP-A 79,022; EP-A 84,164; EP-A 89,637; EP-A 90,341; EP-A 90,362; EP-A 105,102; EP-A 109,020; EP-A 111,873; EP-A 271,865 and EP-A 344,682.
In addition, the amino acids can also be present as esters or amides, such as methyl ester, ethyl ester, isopropyl ester, isobutyl ester, tert-butyl ester, benzyl ester, ethyl amide, semicarbazide or xcfx89-amino-(C2-C8)-alkylamide.
Functional groups of the amino acids can be protected. Suitable protecting groups, such as urethane protecting groups, carboxyl protecting groups and side-chain protecting groups are described in Hubbuch, Kontakte (Merck) 1979, No. 3, pages 14 to 23, and in Bxc3xcllesbach, Kontakte (Merck) 1980, No. 1, pages 23 to 35. Those which may be mentioned in particular are: Aloc, Pyoc, Fmoc, Tcboc, Z, Boc, Ddz, Bpoc, Adoc, Msc, Moc, Z(NO2), Z(Haln), Bobz, Iboc, Adpoc, Mboc, Acm, tert-butyl, OBzl, ONbzl, OMbzl, Bzl, Mob, Pic, Trt.
Physiologically tolerated salts of the compounds of the formula I are in particular pharmaceutically utilizable or nontoxic salts. These salts are formed, for example, from compounds of the formula I which contain acidic groups, for example carboxyl, using alkali metals or alkaline earth metals, such as Na, K, Mg and Ca, and also using physiologically tolerated organic amines, such as triethylamine, ethanolamine or tris-(2-hydroxyethyl)-amine.
Compounds of the formula I which contain basic groups, for example an amino group, an amidino group or a guanidino group, form salts with inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, and with organic carboxylic or sulfonic acids, such as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid.
The novel compounds of the formula I can contain optically active carbon atoms which can, independently of each other, have R or S configurations, and these compounds can consequently be present in the form of pure enantiomers or pure diastereomers or in the form of enantiomeric mixtures or diastereomeric mixtures. Both pure enantiomers and enantiomeric mixtures and also diastereomers and diastereomeric mixtures are part of the subject matter of the present invention.
Over and above this, the novel compounds of the formula I can contain movable hydrogen atoms and can consequently be present in different tautomeric forms. These tautomers are also part of the subject matter of the present invention.
If A, D or F are, independently of each other, xe2x80x94CR2xe2x95x90CR3xe2x80x94, xe2x80x94NR2xe2x80x94Nxe2x95x90CR2xe2x80x94, xe2x80x94Nxe2x95x90CR2xe2x80x94 or xe2x80x94R2Cxe2x95x90Nxe2x80x94 and/or B is xe2x80x94CR2xe2x95x90CR3xe2x80x94, and/or W is R1xe2x80x94Axe2x80x94Bxe2x80x94Dxe2x80x94C(R16)xe2x95x90C or 
the novel compounds of the formula I can be present as E/Z isomeric mixtures. The present invention relates both to pure E or Z isomers and to E/Z isomeric mixtures. Diastereomers, including E/Z isomers, can be separated into the individual isomers by chromatography. Racemates can be separated into the two enantiomers either by chromatography on chiral phases or by racemate resolution.
Compounds of the formula I are preferred in which:
W is R1xe2x80x94Axe2x80x94Bxe2x80x94Dxe2x80x94C(R16), R1xe2x80x94Axe2x80x94Bxe2x80x94Dxe2x80x94C(R16)xe2x95x90C, 
xe2x80x83or 
xe2x80x83where the ring systems 
xe2x80x83contain 1 or 2 heteroatoms from the group N and O, can be saturated or unsaturated once, and can be substituted by 1 or 2 substituents from R16;
Y is Cxe2x95x90O, Cxe2x95x90S or xe2x80x94CH2xe2x80x94;
Z is N(R0), O or xe2x80x94CH2xe2x80x94;
A is a direct linkage, (C1-C6)-alkanediyl, xe2x80x94NR2xe2x80x94Nxe2x95x90CR2xe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94C(O)Oxe2x80x94, xe2x80x94NR2xe2x80x94C(O)Sxe2x80x94, xe2x80x94NR2xe2x80x94C(S)xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94C(S)xe2x80x94Oxe2x80x94, xe2x80x94NR2xe2x80x94C(S)xe2x80x94Sxe2x80x94, xe2x80x94NR2xe2x80x94S(O)nxe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94S(O)nxe2x80x94Oxe2x80x94, xe2x80x94NR2xe2x80x94S(O)nxe2x80x94,(C3-C8)-cycloalkanediyl, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94(C5-C12)-arylene-C(O)xe2x80x94NR2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94(C5-C12)-arylene-, xe2x80x94COxe2x80x94, xe2x80x94(C5-C12)-arylene-COxe2x80x94, xe2x80x94NR2xe2x80x94, xe2x80x94SO2xe2x80x94NR2, xe2x80x94C(O)Oxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94Nxe2x95x90CR2xe2x80x94, xe2x80x94R2Cxe2x95x90Nxe2x80x94, xe2x80x94CR2xe2x95x90CR3xe2x80x94, xe2x80x94(C5-C12)-arylene-S(O)nxe2x80x94, which in each case can be substituted by NR2 and/or be substituted, once or twice, by (C1-C8)-alkanediyl;
B is a direct linkage, (C1-C6)-alkanediyl, (C5-C8)-arylene, (C3-C8)-cycloalkanediyl, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94NR2xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)xe2x80x94NR2xe2x80x94, xe2x80x94S(O)2xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94S(O)xe2x80x94, xe2x80x94NR2xe2x80x94S(O)2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94CR2xe2x95x90CR3xe2x80x94, which in each case can be substituted, once or twice, by (C1-C6)-alkanediyl;
D is a direct linkage, (C1-C8)-alkanediyl, (C5-C8)-arylene, xe2x80x94Oxe2x80x94, xe2x80x94NR2xe2x80x94, xe2x80x94COxe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94COxe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94C(S)xe2x80x94NR2xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CSxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)2xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94S(O)xe2x80x94, xe2x80x94NR2xe2x80x94S(O)2xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CR2xe2x95x90CR3xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94NR2xe2x80x94Nxe2x95x90CR2xe2x80x94, xe2x80x94Nxe2x95x90CR2xe2x80x94 or xe2x80x94R2Cxe2x95x90Nxe2x80x94, which in each case can be substituted, once or twice, by (C1-C6)-alkanediyl, xe2x80x94CR2xe2x95x90CR3xe2x80x94 or (C5-C6)-arylene;
E is a direct linkage, (C1-C4)-alkandeiyl, (C2-C4)-alkenediyl, (C2-C4)-alkynediyl, phenylene, phenylene-(C1-C2)-alkanediyl or (C1-C2)-alkanediylphenylene;
F is defined as D;
G is 
L is C(R16) or N;
R0 is H, (C1-C6)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, (C5-C12)-aryl, (C5-C12)-aryl-(C1-C6)-alkyl, (C1-C8)-alkyl-C(O), (C3-C8)-cycloalkyl-C(O), (C3-C8)-cycloalkyl-(C1-C4)-alkyl-C(O), (C5-C12)-aryl-C(O) or (C5-C12)-aryl-(C1-C4)-alkyl-C(O), where the alkyl radicals can be substituted, once or more than once, by fluorine;
R1 is R2xe2x80x94C(xe2x95x90NR2)NR3xe2x80x94, R2R3Nxe2x80x94C(xe2x95x90NR2)xe2x80x94, R2R3 Nxe2x80x94C(xe2x95x90NR2)xe2x80x94NR2, or a 4-10-membered, monocyclic or polycyclic, aromatic or non-aromatic ring system which can optionally contain 1-4 heteroatoms from the group N, O and S and can optionally be substituted, once or more than once, by substituents from the group R12, R13, R14 and R15;
R2 and R3 are, independently of each other, H, (C1-C8)-alkyl which is optionally substituted, once or more than once, by fluorine, (C3-C8)cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, (C5-C12)-aryl, (C5-C12)-aryl-(C1-C6)-alkyl, H2N, R8ONR9, R8OR9, R8OC(O)R9, R8xe2x80x94(C5-C12)-aryl-R9, R8 R8NR9, HOxe2x80x94(C1-C8)-alkyl-NR8R9, R8R8NC(O)R9, R8C(O)NR8R9, R8C(O)R9, R8R8Nxe2x80x94C(xe2x95x90NR8)xe2x80x94, R8R8Nxe2x80x94C(xe2x95x90NR8)xe2x80x94NR8xe2x80x94 or (C1-C10)-alkylcarbonyloxy-(C1-C4)-alkoxycarbonyl;
R4, R5, R6 and R7 are, independently of each other, H, fluorine, OH, (C1-C8)-alkyl, (C5-C12)-cycloalkyl, (C5-C12)-cycloalkyl-(C1-C8)-alkyl, or R8OR9, R8 SR9, R8CO2R9, R8OC(O)R9, R8xe2x80x94(C5-C12)-aryl-R9, R8N(R2)R9, R8R8NR9, R8N(R2)C(O)OR9, R8S(O)nN(R2)R9, R8OC(O)N(R2)R9, R8C(O)N(R2)R9, R8N(R2)C(O)N(R2)R9, R8N(R2)S(O)nN(R2)R9, R8S(O)nR9, R8SC(O)N(R2)R9, R8C(O)R9, R8N(R2)C(O)R5, R8N(R2)S(O)nR9;
R8 is H, (C1-C6)-alkyl, (C5-C12)-cycloalkyl, (C5-C12)-cycloalkyl-(C1-C6)-alkyl, (C5-C12)-aryl or (C5-C12)-aryl-(C1-C6)-alkyl, where the alkyl radicals can be substituted, once or more than once, by fluorine;
R9 is a direct linkage or (C1-C6)-alkanediyl;
R10 is C(O)R11, C(S)R11, S(O)nR11, P(O)nR11 or a 4- to 8-membered, saturated or unsaturated heterocycle which contains 1, 2, 3 or 4 heteroatoms from the group N, O and S;
R11 is OH, (C1-C6)-alkoxy, (C5-C12)-aryl-(C1-C6)-alkoxy, (C5-C12)-aryloxy, (C1 -C6)-alkylcarbonyloxy-(C1-C4)-alkoxy, (C5-C12)-aryl-(C1-C6)-alkylcarbonyloxy-(C1-C6)-alkoxy, NH2, mono- or di(C1-C6-alkyl)amino, (C5-C12)-aryl-(C1-C6)-alkylamino or (C1-C6)-dialkylaminocarbonylmethyloxy;
R12, R13, R14 and R15 are, independently of each other, H, (C1-C8)-alkyl, which is optionally substituted, once or more than once, by fluorine, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, (C5-C12)-aryl, (C5-C12)-aryl-(C1-C6)-alkyl, H2N, R8ONR9, R8OR9, R8OC(O)R9, R8xe2x80x94(C5-C12)-aryl-R9, R8R8NR9, HOxe2x80x94(C1-C8)-alkyl-N(R2)R9, R8N(R2)C(O)R9, R8C(O)N(R2)R9, R8C(O)R9, R2R3Nxe2x80x94C(xe2x95x90NR2)xe2x80x94, R2R3Nxe2x80x94C(xe2x95x90NR3)xe2x80x94NR2xe2x80x94, xe2x95x90O or xe2x95x90S; where two adjacent substituents from R12 to R15 can also together be xe2x80x94OCH2Oxe2x80x94, xe2x80x94OCH2CH2Oxe2x80x94 or xe2x80x94OC(CH3)2Oxe2x80x94;
R16 is H, (C1-C8)-alkyl which is optionally substituted, once or more than once, by fluorine, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, (C5-C12)-aryl, (C5-C12)-aryl-(C1-C6)-alkyl, (C2-C8)-alkenyl or (C2-C8)-alkynyl;
m is 3, 4 or 5;
n is 1 or 2; and
p and q are, independently of each other, 0 or 1,
and the physiologically tolerated salts thereof.
Compounds of the formula I are particularly preferred in which:
W is R1xe2x80x94Axe2x80x94Bxe2x80x94Dxe2x80x94C(R16), R1xe2x80x94Axe2x80x94Bxe2x80x94Dxe2x80x94C(R16)xe2x95x90C or 
Y is Cxe2x95x90O, Cxe2x95x90S or xe2x80x94CH2xe2x80x94; preferably Cxe2x95x90O or Cxe2x95x90S;
Z is N(R0) or xe2x80x94CH2xe2x80x94; preferably N(R0);
A is a direct linkage, (C1-C6)-alkanediyl, xe2x80x94NR2xe2x80x94Nxe2x95x90CR2xe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94C(O)Oxe2x80x94, xe2x80x94NR2xe2x80x94C(O)Sxe2x80x94, xe2x80x94NR2xe2x80x94S(O)nxe2x80x94NR2xe2x80x94, xe2x80x94NR2 xe2x80x94S(O)nxe2x80x94, (C3-C6)-cycloalkanediyl, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94(C5-C10)-arylene-C(O)xe2x80x94NR2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94(C5-C10)-arylene-, xe2x80x94COxe2x80x94, (C5-C10)-arylene-COxe2x80x94, xe2x80x94NR2 xe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94Nxe2x95x90CR2xe2x80x94, xe2x80x94R2Cxe2x95x90Nxe2x80x94 or xe2x80x94CR2xe2x95x90CR3xe2x80x94, which in each case can be substituted by NR2 and/or be substituted, once or twice, by (C1-C6)-alkanediyl;
B is a direct linkage, (C1-C6)-alkanediyl, (C5-C6)-arylene, (C5-C6)-cycloalkanediyl, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94S(O)2xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94CR2xe2x95x90CR3xe2x80x94, which in each case can be substituted, once or twice, by (C1-C6)-alkanediyl;
D is a direct linkage, (C1-C6)-alkanediyl, (C5-C6)-arylene, xe2x80x94Oxe2x80x94, xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94COxe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94C(S)xe2x80x94NR2, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94S(O)xe2x80x94, xe2x80x94NR2xe2x80x94S(O)2xe2x80x94, xe2x80x94Nxe2x95x90CR2xe2x80x94 or xe2x80x94R2Cxe2x95x90Nxe2x80x94, which in each case can be substituted, once or twice, by (C1-C6)-alkanediyl;
E is a direct linkage, (C1-C4)-alkanediyl or (C2-C4)-alkenediyl;
F is a direct linkage, (C1-C6)-alkanediyl, xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94COxe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)2xe2x80x94NR2xe2x80x94, xe2x80x94NR2 xe2x80x94S(O)2xe2x80x94, xe2x80x94CR2xe2x95x90CR3xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Nxe2x95x90CR2xe2x80x94 or xe2x80x94R2Cxe2x95x90Nxe2x80x94, which in each case can be substituted, once or twice, by (C1-C6)-alkanediyl;
G is 
L is C(R16) or N;
R0 is H, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C3-C6)-cycloalkyl-(C1-C4)-alkyl, (C5-C10)-aryl, (C5-C10)-aryl-(C1-C4)-alkyl, (C1-C6)-alkyl-C(O)xe2x80x94, (C5 -C6)-cycloalkylmethyl-C(O)xe2x80x94, phenyl-C(O) or benzyl-C(O), where the alkyl radicals can be substituted by 1-6 fluorine atoms;
R1 is R2C(xe2x95x90NR2)NR2xe2x80x94, R2R3Nxe2x80x94C(xe2x95x90NR2)xe2x80x94, 
with Yxe2x80x2 being NR2, O or S.
R2 and R3 are, independently of each other, H, (C1-C6)-alkyl which is optionally substituted, once or more than once, preferably 1-6 times, by fluorine, (C3-C6)-cycloalkyl, (C3-C6)-cycloalkyl-(C1-C4)-alkyl, (C5-C10)-aryl, (C5-C10)-aryl-(C1-C4)-alkyl, H2N, R8OR9, R8xe2x80x94(C5-C10)-aryl-R9, R8NHR9, R8R8NR9, R8NHC(O)R9, R8C(O)xe2x80x94, H2Nxe2x80x94C(xe2x95x90NH) or H2Nxe2x80x94C(xe2x95x90NH)xe2x80x94NHxe2x80x94;
R4, R5, R6 and R7 are, independently of each other, H, fluorine, OH, (C1-C6)-alkyl, (C6-C12)-cycloalkyl, (C6-C12)-cycloalkyl-(C1-C6)-alkyl, or R8OR9, R8 CO2R9, R8OC(O)R9, R8xe2x80x94(C5-C10)-aryl-R9, R8NHR9, R8R8NR9, R8NHC(O)OR9, R8S(O)nNHR9, R8OC(O)NHR9, R8C(O)NHR9, R8C(O)R9, R8NHC(O)NHR9, R8NHS(O)nNHR9, R8NHC(O)R9, R8NHS(O)nR9;
R8 is H, (C1-C6)-alkyl, (C6-C12)-cycloalkyl, (C6-C12)-cycloalkyl-(C1-C4)alkyl (C5 -C10)-aryl or (C5-C10)-aryl-(C1-C4)-alkyl, where the alkyl radicals can be substituted by 1-6 fluorine atoms;
R9 is a direct linkage or (C1-C6)-alkanediyl;
R10 is C(O)R11, S(O)nR11 or P(O)nR11;
R11 is OH, (C1-C6)-alkoxy, (C5-C10)-aryl-(C1-C6)-alkoxy, (C5-C10)-aryloxy, (C1 -C6)-alkylcarbonyloxy-(C1-C4)-alkoxy, (C5-C10)-aryl-(C1-C4)-alkylcarbonyloxy-(C1-C4)-alkoxy, NH2 or mono- or di(C1-C6-alkyl)amino;
R12, R13 and R14 are H, (C1-C6)-alkyl, which is optionally substituted, once or more than once, by fluorine, (C3-C6)-cycloalkyl, (C3-C6)-cycloalkyl-(C1-C4)-alkyl, (C5-C10)-aryl, (C5-C10)-aryl-(C1-C4)-alkyl, H2N, R8OR9, R8 OC(O)R9, R8xe2x80x94(C5 -C10)-aryl-R9, R8R8NR9, R8NHC(O)R9, R8C(O)NHR9, H2Nxe2x80x94C(xe2x95x90NH)xe2x80x94, H2Nxe2x80x94C(xe2x95x90NH)xe2x80x94NHxe2x80x94 or xe2x95x90O;
xe2x80x83where two adjacent substituents from R12-R14 can also together be xe2x80x94OCH2xe2x80x94 or xe2x80x94OCH2CH2Oxe2x80x94;
R16 is H, (C1-C6)-alkyl which can be substituted 1-6 times by fluorine, (C3-C6)-cycloalkyl, (C3-C6)-cycloalkyl-(C1-C4)-alkyl, phenyl, phenyl-(C1-C4)-alkyl or (C2-C6)-alkenyl;
m is 3, 4 or 5;
n is 1 or 2; and
p and q are, independently of each other, 0 or 1,
and the physiologically tolerated salts thereof.
Compounds of the formula I are very particularly preferred in which:
W is R1xe2x80x94Axe2x80x94Bxe2x80x94Dxe2x80x94C(R16) or R1xe2x80x94Axe2x80x94Bxe2x80x94Dxe2x80x94CHxe2x95x90C;
Y is Cxe2x95x90O or Cxe2x95x90S;
Z is N(R0);
A is a direct linkage, (C1-C4)-alkanediyl, xe2x80x94NR2xe2x80x94Nxe2x95x90CR2xe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94C(O)Cxe2x80x94, xe2x80x94NR2xe2x80x94S(O)nxe2x80x94, xe2x80x94NR2xe2x80x94S(O)nxe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94COxe2x80x94, xe2x80x94NR2xe2x80x94 or xe2x80x94Nxe2x95x90CR2, which in each case can be substituted by NH and/or be substituted, once or twice, by (C1-C4)-alkanediyl;
B is a direct linkage, (C1-C4)-alkanediyl, phenylene, a divalent radical of pyridine, thiophene or furane, cyclohexanediyl, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CR2xe2x95x90CR3xe2x80x94, xe2x80x94C(O)xe2x80x94NR2xe2x80x94 or xe2x80x94NR2xe2x80x94C(O)xe2x80x94, which in each case can be substituted, once or twice, by (C1-C4)-alkanediyl;
D is a direct linkage, (C1-C4)-alkanediyl, phenylene, xe2x80x94Oxe2x80x94, xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94COxe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94R2Nxe2x80x94S(O)2xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94S(O)2xe2x80x94, xe2x80x94NR2xe2x80x94S(O)xe2x80x94, xe2x80x94Nxe2x95x90CR2xe2x80x94 or xe2x80x94R2Cxe2x95x90Nxe2x80x94, which in each case can be substituted, once or twice, by (C1-C4)-alkanediyl;
E is a direct linkage or (C1-C4)-alkanediyl;
F is a direct linkage, (C1-C6)-alkanediyl, xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94COxe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94S(O)2xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94S(O)2xe2x80x94, xe2x80x94CR2xe2x95x90CR3xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Nxe2x95x90CR2xe2x80x94 or xe2x80x94R2Cxe2x95x90Nxe2x80x94, which in each case can be substituted, once or twice, by (C1-C4)-alkanediyl;
G is 
R0 is H, (C1-C6)-alkyl, trifluoromethyl, pentafluoroethyl, (C5-C6)-cycloalkyl, (C5 -C6)-cycloalkyl-(C1-C2)-alkyl, optionally substituted phenyl or benzyl which is optionally substituted on the phenyl radical;
R1 is R2R3Nxe2x80x94C(xe2x95x90NR2), 
with Yxe2x80x2 being NH, O or S.
R2 and R3 are, independently of each other, H, (C1-C6)-alkyl, trifluoromethyl, pentafluoroethyl, (C5-C6)-cycloalkyl, (C5-C6)-Cycloalkyl-(C1-C2)-alkyl, phenyl, benzyl, H2N, R8OR9, R8xe2x80x94(C5-C10)-aryl-R9, R8NHR9, R8R8NR9, R8NHC(O)R9, H2Nxe2x80x94C(xe2x95x90NH) or H2Cxe2x80x94C(xe2x95x90NH)xe2x80x94NHxe2x80x94;
R4, R5, R6 and R7 are, independently of each other, H, fluorine, OH, (C1-C6)-alkyl, (C10-C12)-cycloalkyl, (C10-C12)-cycloalkyl-(C1-C6)-alkyl, or R8OR9, R8-(C5 -C10)-aryl-R9, R8R8NR9, R8NHC(O)OR9, R8S(O)nNHR9, R8 OC(O)NHR9 or R8C(O)NHR9;
R8 is H, (C1-C6)-alkyl, (C10-C12)-cycloalkyl, (C10-C12)-cycloalkyl-(C1 -C2)-alkyl, (C5-C10)-aryl or (C5-C10)-aryl-(C1-C2)-alkyl;
R9 is a direct linkage or (C1-C6)-alkanediyl;
R10 is C(O)R11;
R11 is OH, (C1-C6)-alkoxy, phenoxy, benzyloxy, (C1-C4)-alkylcarbonyloxy-(C1-C4)-alkoxy, NH2, mono- or di(C1-C6-alkyl)amino;
R16 is H, (C1-C4)-alkyl, trifluoromethyl, pentafluoroethyl, (C5-C6)cycloalkyl, (C5 -C6)-cycloalkyl-(C1-C2)-alkyl, phenyl or benzyl;
n is 1 or 2; and
p and q are, independently of each other, 0 or 1,
and the physiologically tolerated salts thereof.
Compounds of the formula I are furthermore preferred in which R0 is hydrogen, and the physiologically tolerated salts thereof.
Abbreviations Employed:
Boc: t-butoxycarbonyl
DCCl: dicyclohexylcarbodiimide
DMF: dimethylformamide
HOOBt: 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine
THF: tetrahydrofuran
HOBt: 1-hydroxybenzotriazole
TOTU O-[cyano(ethoxycarbonyl)methylenamino]-1,1,3,3-tetramethyluronium tetrafluoroborate
DIPEA: diisopropylethylamine
RT: room temperature
Z: benzyloxycarbonyl
In general, compounds of the formula I can be prepared, for example in the course of a conversion synthesis, by linking two or more fragments which can be derived retrosynthetically from the formula I. In general, when the compounds of the formula I are being prepared, it may be necessary, during the course of the synthesis, to temporarily block functional groups, which might give rise, in the particular synthesis step, to undesirable reactions or side reactions, by means of a protecting group strategy which is adapted to the synthesis problem, an approach with which the skilled person is familiar. The method of fragment linkage is not restricted to the subsequent examples but, on the contrary, can be applied generally for synthesizing the compounds of the formula I.
For example, compounds of the formula I of the type 
in which F is C(O)NR2, can be prepared by condensing a compound of the formula II 
where M is hydroxycarbonyl, (C1-C6)-alkoxycarbonyl, activated carboxylic acid derivatives, such as acid chlorides, active esters or mixed anhydrides, with HNR2xe2x80x94G.
In order to condense two fragments with the formation of an amide bond, use is advantageously made of coupling methods of peptide chemistry which are known per se (see, for example, Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], Volumes 15/1 and 15/2, Georg Thieme Verlag, Stuttgart, 1974). For this purpose, it is necessary, as a rule, for nonreacting amino groups which are present to be protected during the condensation by means of reversible protecting groups. The same applies to carboxyl groups which are not involved in the reaction, which groups are preferably employed as (C1-C6)-alkyl, benzyl or tert-butyl esters. Amino group protection is no longer necessary when the amino groups which are to be generated are still present as nitro groups or cyano groups and are only formed, by hydrogenation, after the coupling. After the coupling, the protecting groups which are present are eliminated in an appropriate manner. For example, NO2 groups (guanidino protection), benzyloxycarbonyl groups and benzyl esters can be removed by hydrogenation. The protecting groups of the tert-butyl type are eliminated under acid conditions, while the 9-fluorenylmethyloxycarbonyl radical is removed using secondary amines.
Compounds of the formula I, in which 
is a dioxo- or thiooxo-oxo-substituted imidazolidine ring, in which W is R1xe2x80x94Axe2x80x94Bxe2x80x94Dxe2x80x94C(R16), can, for example, be obtained:
by reacting xcex1-amino acids or N-substituted xcex1-amino acids, or preferably their esters, for example the methyl ester, ethyl ester, tert-butyl ester or benzyl ester, for example a compound of the formula III 
xe2x80x83with an isocyanate or isothiocyanate, for example of the formula Uxe2x80x94Exe2x80x94Fxe2x80x94G, in which U is isocyanato, isothiocyanato or trichloromethylcarbonylamino, with urea derivatives or thiourea derivatives of the formula IV, 
in which V is oxygen or sulfur, being obtained, which derivatives are cyclized into compounds of the formula I of the type 
by heating them with acid, with hydrolysis of the ester function.
An example of another method for preparing compounds of the formula I, in which Y is Cxe2x95x90O or Cxe2x95x90S and W is R1xe2x80x94Axe2x80x94Bxe2x80x94Dxe2x80x94C(R16), is the reaction of compounds of the formula V 
with phosgene, thiophosgene or corresponding equivalents (in analogy with S. Goldschmidt and M. Wick, Liebigs Ann. Chem. 575 (1952), 217-231 and C. Tropp, Chem. Ber. 61 (1928), 1431-1439).
Compounds of the formula I in which 
is a heterocycle of the type 
in which Y is Cxe2x95x90O or Cxe2x95x90S and W is R1xe2x80x94Axe2x80x94Bxe2x80x94Dxe2x80x94C(R16)xe2x95x90C, are prepared, for example, in accordance with the following scheme 1: 
U is xe2x80x94NCO or xe2x80x94NCS; V is O or S.
The conversion of compounds of the formula VI into compounds of the formula VII, and of compounds of the formula VII into compounds of the formula VIII, can be effected, for example, in analogy with S. Chung-gi et al., Tetrahedron Lett 1987, 28 (33), 3827 or U. Schmidt et al. Angew. Chemie 1984, 53.
Another option for preparing compounds of the formula VIII consists, for example, in initially cyclizing compounds of the formula VII, under the influence of acid, to form compounds of the formula XII 
and subsequently reacting compounds of the formula XII, in a Horner-Emmons reaction, with 
to form compounds of the formula VIII.
Compounds of the formula I, in which 
is a heterocycle of the type 
in which W is 
can be prepared, for example, in accordance with the following scheme 2: 
Q is a leaving group which can be substituted nucleophilically, such as halogen, mesylate, tosylate, etc.
The conversion of compounds of the formula IX into compounds of the formula X can be effected, for example, in analogy with E. Marinez et al., Helv. Chim. Acta 1983, 66 (1), 338 or E. W. Logusch et al., J. Org. Chem. 1988, 53 (17), 4069.
Compounds of the formula I in which 
is a heterocycle of the type 
in which Y is Cxe2x95x90O or Cxe2x95x90S and W is 
can be prepared, for example, in accordance with the following scheme 3: 
U is xe2x80x94NCO or xe2x80x94NCS; V is O or S.
Another option for preparing compounds of the formula XIII consists, for example, in cyclizing compounds of the formula VII, under the influence of acid, to form compounds of the formula XII and subsequently reacting compounds of the formula XII, in a Horner-Emmons reaction, with 
to form compounds of the formula XIII.
However, in the course of a conversion synthesis, it can be advantageous, depending on the meaning of the individual substituents R1, A, B, D etc., to assemble first of all the heterocyclic ring system, which carries only some of the substituents, and then to introduce the remaining substituents, for example in the course of a fragment linkage. As an example, mention may be made here of the synthesis of Example 1: 
However, this general principle is not restricted to this one example, but rather is generally applicable.
Compounds of the formula I in which R1xe2x80x94A is 
or cyclic guanylhydrazones of the type 
are prepared, for example, by condensing 
with ketones or aldehydes of the type Oxe2x95x90C(R2)xe2x80x94, or corresponding acetals or ketals, using methods from the current literature, for example in analogy with N. Desideri et al., Arch. Pharm. 325 (1992) 773-777 or A. Alves et al., Eur. J. Med. Chem. Chim. Ther. 21 (1986) 297-304.
Where appropriate, the above guanylhydrazones can be obtained as E/Z isomeric mixtures, which can be resolved using current chromatographic methods.
Compounds of the formula I in which R1xe2x80x94A is R2xe2x80x94C(xe2x95x90NR2)NR2xe2x80x94Nxe2x95x90C(R2)xe2x80x94 or a system of the type 
which contains a monocycle or polycycle can be obtained in an analogous manner.
Compounds of the formula I in which R10 is SO2R11 are prepared, for example, by oxidizing compounds of the formula I in which R10 is SH, using methods which are known from the literature (cf. Houben-Weyl, Methoden der Organischen Chemie, Vol. E12/2, Georg Thieme Verlag, Stuttgart 1985, p. 1058ff), to give compounds of the formula I in which R10 is SO3H, from which the compounds of the formula I in which R10 is SO2R11 (R11xe2x89xa0OH) are then prepared either directly or by way of the corresponding sulfonic acid halides by esterification or attaching an amide bond. If necessary, oxidation-sensitive groups in the molecule, such as amino, amidino or guanidino groups, are protected with suitable protecting groups before carrying out the oxidation.
Compounds of the formula I in which R10 is S(O)R11 are prepared, for example, by converting compounds of the formula I in which R10 is SH into the corresponding sulfide (R10 is Sxe2x8ax96) and subsequently oxidizing them with meta-chloroperbenzoic acid to form the sulfinic acids (R10 is SO2H) (cf. Houben-Weyl, Methoden der Organischen Chemie, Vol. E11/1, Georg Thieme Verlag, Stuttgart 1985, p. 618f), from which the corresponding sulfinic esters or amides, R10 is S(O)R11 (R11xe2x89xa0OH), can be prepared using the methods which are known from the literature. In general, use can also be made of other methods known from the literature for preparing compounds of the formula I in which R10 is S(O)nR11 (n is 1 or 2) (cf. Houben-Weyl, Methoden der Organischen Chemie, Vol. E11/1, Georg Thieme Verlag, Stuttgart 1985, p. 618ff or Vol. E11/2, Stuttgart 1985, p. 1055ff).
Compounds of the formula I in which R10 is P(O)Rn11 (n is 1 or 2) are synthesized from suitable precursors using methods which are known from the literature (cf. Houben-Weyl, Methoden der Organischen Chemie, Vols. E1 and E2, Georg Thieme Verlag, Stuttgart 1982), with the synthesis method which is selected having to be adapted to the target molecule.
Compounds of the formula I in which R10 is C(S)R11 can be prepared using methods which are known from the literature (cf. Houben-Weyl, Methoden der Organischen Chemie, Vol. E5/1 and E5/2, Georg Thieme Verlag, Stuttgart 1985).
Naturally, compounds of the formula I in which R10 is S(O)nR11 (n is 1 or 2), P(O)R11n (n is 1 or 2) or C(S)R11 can also be prepared by fragment linkage, as described above, which is advisable, for example, when Exe2x80x94Fxe2x80x94G of the formula I contains, for example, a (commercially available) aminosulfonic acid, aminosulfinic acid, aminophosphonic acid or aminophosphinic acid, or derivatives thereof, such as esters or amides.
Compounds of the formula I in which R1xe2x80x94A is 
or cyclic acylguanidines of the typ 
can be prepared, for example, by reacting a compound of the formula I in which W is Q(O)Cxe2x80x94Bxe2x80x94Dxe2x80x94C(R16)xe2x80x94 or Q(O)Cxe2x80x94Bxe2x80x94Dxe2x80x94C(R16)xe2x95x90C or 
and Q is a leaving group which can be readily substituted nucleophilically, with the corresponding guanidine (derivative) of the type 
or cyclic guanidine (derivative) 
The above activated acid derivatives of the type Q(O)C, in which Q is an alkoxy group, preferably a methoxy group, a phenoxy group, a phenylthio group, a methyithio group, a 2-pyridylthio group or a nitrogen heterocycle, preferably 1-imidazolyl, are advantageously obtained, in a manner known per se, from the underlying carbonyl chlorides, Q is Cl, which, for their part, can in turn be prepared, in a manner known per se, from the underlying carboxylic acids, Q is OH, for example using thionyl chloride.
In addition to the carbonyl chlorides (Q is Cl), other activated acid derivatives of the A type Q(O)Cxe2x80x94 can also be prepared, in a manner known per se, directly from the underlying carboxylic acids (Q is OH), such as, for example, the methyl esters (Q is OCH3) by treating with gaseous HCl in methanol, the imidazolides (Q is 1-imidazolyl) by treating with carbonyldiimidazole [cf. Staab, Angew. Chem. Int. Ed. Engl. 1, 351-367 (1962)], and the mixed anhydrides (Q is C2H5OC(O)O or TosO) using Cl-COOC2H5 or tosyl chloride, respectively, in the presence of triethylamine in an inert solvent. The carboxylic acids can also be activated with dicyclohexylcarbodiimide (DCCl) or with O-[(cyano(ethoxycarbonyl)methylen)amino]-1,1,3,3-tetramethyluronium-tetrafluoroborate (xe2x80x9cTOTUxe2x80x9d) [Weiss and Krommer, Chemiker Zeitung 98, 817 (1974)] and other activating reagents which are customary in peptide chemistry. A series of suitable methods for preparing activated carboxylic acid derivatives of the formula II is given, with citation of the source literature, in J. March, Advanced Organic Chemistry, Third Edition (John Wiley and Sons, 1985), p. 350.
The reaction of an activated carboxylic acid derivative of the type Q(O)Cxe2x80x94 with the respective guanidine (derivative) is effected, in a manner known per se, in a protic or aprotic, polar but inert organic solvent. In this context, methanol, isopropanol or THF, at a temperature of from 20xc2x0 C. up to the boiling temperature of the solvents, have proved to be of value when reacting the methyl esters (Q is OMe) with the respective guanidines. Most reactions of compounds of the type Q(O)Cxe2x80x94 with salt-free guanidines are advantageously carried out in aprotic, inert solvents such as THF, dimethoxyethane and dioxane. However, when a base (such as NaOH) is employed, water can also be used as solvent when reacting Q(O)Cxe2x80x94 with guanidines.
When Q is Cl, the reaction is advantageously carried out in the presence of an added acid-capturing agent, for example in the form of excess guanidine (derivative), for the purpose of binding and removing the hydrohalic acid.
Compounds of the formula I in which R1xe2x80x94A is 
or a system of the type 
containing a monocycle or polycycle can be obtained in an analogous manner.
Compounds of the formula I in which R1xe2x80x94A is a sulfonyl guanidine or sulfoxyl guanidine of the type R2R3Nxe2x80x94C(xe2x95x90NR2)xe2x80x94NR2xe2x80x94S(O)n (n is 1 or 2) or 
(n is 1 or 2) are prepared, using methods known from the literature, by reacting R2R3Nxe2x80x94C(xe2x95x90NR3)NR2H or 
with sulfinic acid derivatives or sulfonic acid derivatives of the formula I in which W is Qxe2x80x94S(O)nxe2x80x94Bxe2x80x94Dxe2x80x94C(R16)xe2x80x94 or Qxe2x80x94S(O)nxe2x80x94Bxe2x80x94Dxe2x80x94C(R16)xe2x95x90C or 
and Q is, for example, Cl or NH2, in analogy with S. Birtwell et al., J. Chem. Soc. (1946) 491 or Houben Weyl, Methoden der Organischen Chemie, Vol. E4, Georg Thieme Verlag, Stuttgart 1983; p. 620 ff.
Compounds of the formula I in which R1A is R2xe2x80x94C(xe2x95x90NR2)NR2xe2x80x94S(O)n (n is 1 or 2) or a system of the type 
containing a monocycle or polycycle (n is 1 or 2) can be obtained in an analogous manner.
Compounds of the formula I in which A is xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94C(O)Oxe2x80x94 or xe2x80x94NR2xe2x80x94C(O)Sxe2x80x94 and R1 is R2R3Nxe2x80x94C(xe2x95x90NR2), R2xe2x80x94C(xe2x95x90NR2) or a 4-14-membered monocyclic or polycyclic, aromatic or non-aromatic ring system, which is specified as described on page 6 and can be substituted as described on that page, are prepared, for example, by first of all reacting a compound of the formula I, in which W is Qxe2x80x94Bxe2x80x94Dxe2x80x94C(R16)xe2x80x94 or Qxe2x80x94Bxe2x80x94Dxe2x80x94C(R16)xe2x95x90C or 
and Q is HNR2xe2x80x94, HOxe2x80x94 or HSxe2x80x94, with a suitable carbonic acid derivative, preferably phosgene, diphosgene (trichloromethyl chloroformate), triphosgene (bis(trichloromethyl)carbonate), ethyl chloroformate, i-butyl chloroformate, bis-(1-hydroxy-1-H-benzotriazolyl)carbonate or N,Nxe2x80x2-carbonyldiimidazole, in a solvent which is inert towards the reagents employed, preferably DMF, THF or toluene, at a temperature of between xe2x88x9220xc2x0 C. and the boiling point of the solvent, preferably between 0xc2x0 C. and 60xc2x0 C., to form a substituted carbonic acid derivative of the formula I, in which W is 
R is xe2x80x94NR2xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 and Qxe2x80x2 is chlorine, ethoxy, isobutoxy, benzotriazol-1-oxy or 1-imidazolyl, depending on the carbonic acid derivative employed.
The reaction of these derivatives with R2R3Nxe2x80x94C(xe2x95x90NR2)xe2x80x94NR2H or R2xe2x80x94C(xe2x95x90NR2)xe2x80x94NR2H or with the systems of the type 
containing a monocycle or polycycle are effected as described above in association with the preparation of acylguanidine (derivatives).
Compounds of the formula I, in which F is R2Nxe2x80x94C(O)xe2x80x94NR2 or R2Nxe2x80x94C(S)xe2x80x94NR2, are prepared, for example, by reacting a compound of the type 
with an isocyanate OCNxe2x80x94G or isothiocyanate SCNxe2x80x94G using methods which are known from the literature.
Compounds of the formula I, in which F is C(O)NR2, xe2x80x94SO2NR2xe2x80x94 or xe2x80x94C(O)Oxe2x80x94, can be obtained, for example, by reacting 
(Q is a leaving group which can readily be substituted nucleophilically, such as OH, Cl, OMe etc.) with HR2Nxe2x80x94G or HOxe2x80x94G in accordance with methods which are known from the literature.
Compounds of the formula I, in which R1xe2x80x94A comprises a monocycle or polycycle of the type 
can, for example, be prepared by reacting a compound of the formula I, in which W is HR2Nxe2x80x94Bxe2x80x94Dxe2x80x94C(R16)xe2x80x94 or HR2Nxe2x80x94Bxe2x80x94Dxe2x80x94C(R16)xe2x95x90C or 
with a monocycle or polycycle of the type 
in which X is a leaving group which can be substituted nucleophilically, such as halogen or SH, SCH3, SOCH3, SO2CH3, SO3H or HNxe2x80x94NO2 using methods which are known from the literature (see, for example, A. F. Mckay et al., J. Med. Chem. 6 (1963) 587, M. N. Buchman et al., J. Am. Chem. Soc. 71 (1949), 766, F. Jung et at., J. Med. Chem. 34 (1991) 1110 or G. Sorba et al., Eur. J. Med. Chem. 21 (1986), 391).
Compounds of the formula I, in which R1A comprises a monocycle or polycycle of the type 
can be prepared, for example, by reacting a compound of the formula I, in which W is HR2Nxe2x80x94Bxe2x80x94Dxe2x80x94C(R16)xe2x80x94 or HR2Nxe2x80x94Bxe2x80x94Dxe2x80x94C(R16)xe2x95x90C or 
with a compound of the type 
in which X is a leaving group, such as xe2x80x94SCH3, using methods which are known from the literature (cf., e.g., T. Hiroki et al., Synthesis (1984) 703 or M. Purkayastha et al., Indian J. Chem. Sect. B 30 (1991) 646).
Compounds of the formula I in which R1A is a bis-aminotriazole or a bis-aminooxadiazole radical, can be prepared, for example, as described by P. J. Garrett et al., Tetrahedron 49 (1993) 165 or R. Lee Webb et al., J. Heterocyclic Chem. 24 (1987) 275 in accordance with the following reaction sequence: 
Preparation methods which are known from the literature are described, for example, in J. March, Advanced Organic Chemistry, Third Edition (John Wiley and Sons, 1985).
Another embodiment of the instant invention includes a pharmaceutical composition containing a vitronectin receptor antagonistic amount of the compounds of formula I and a pharmaceutically acceptable carrier. By antagonistic amount it is meant an amount effective to curtail or prevent binding of natural ligand to vitronectin receptor, thereby preventing or ameliorating diseases or conditions associated with such binding. This amount is determined on a case by case basis depending on variables well known to the skilled artisan, such as the nature and state of the disease or condition, and the age and weight and physical condition of the recipient of the pharmaceutical.
The instant invention further includes a method of treating a disease or condition associated with vitronectin receptor binding comprising administering to a mammal this pharmaceutical composition. By treatment it is meant preventing, alleviating, or otherwise ameliorating diseases or conditions associated with vitronectin receptor binding. Such diseases and conditions include but are not limited to bone reabsorption by osteoclasts, tumor growth and tumor metastasis, inflammation, cardiovascular diseases, nephropathies and retinopathies.
Thus in one embodiment, the compounds of the formula I, and their physiologically tolerated salts, may be administered to animals, preferably mammals, and in particular humans, as medicaments, either alone, in mixtures with each other, or in the form of pharmaceutical preparations which permit enteral or parenteral use and which comprise, as the active constituent, an effective dose of at least one compound of the formula I, or a salt thereof, in addition to the customary pharmaceutically unobjectionable carrier substances and auxiliary substances. The preparations normally comprise from about 0.5 to 90% by weight of the therapeutically active compound.
The medicaments may be administered orally, for example in the form of pills, tablets, lacquer tablets, coated tablets, granules, hard gelatin capsules, soft gelatin capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures. However, the administration can also be effected rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions or infusion solutions, microcapsules or rods, percutaneously, for example in the form of ointments or tinctures, or nasally, for example in the form of nasal sprays.
The pharmaceutical preparations are produced in a manner known per se, using pharmaceutically inert inorganic or organic carrier substances. For example, lactose, cornstarch or derivatives thereof, talc, stearic acid or its salts, etc. can be used for preparing pills, tablets, coated tablets and hard gelatin capsules. Examples of carrier substances for soft gelatin capsules and suppositories are fats, waxes, semisolid and liquid polyols, natural or hardened oils, etc. Examples of suitable carrier substances for preparing solutions and syrups are water, sucrose, invert sugar, glucose, polyols, etc. Suitable carrier substances for preparing injection solutions are water, alcohols, glycerol, polyols, vegetable oils, etc. Suitable carrier substances for microcapsules, implants or rods are mixed polymers composed of glycolic acid and lactic acid.
In addition to the active compounds and carrier substances, the pharmaceutical preparations can also comprise additives, such as filters, extenders, disintegrants, binders, glidants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, dyes, flavorants or aromatizing agents, thickeners, diluents and buffering substances, and also solvents or solubilizers or agents for achieving a slow-release effect, and also salts for altering the osmotic pressure, coating agents or antioxidants. They can also comprise two or more compounds of the formula I or their physiologically tolerated salts; they can furthermore comprise one or more different therapeutically active compounds in addition to at least one compound of the formula I.
The dose can vary within wide limits and has to be adjusted to the individual circumstances in each individual case.
In the case of oral administration, the daily dose can be from 0.01 to 50 mg/kg, preferably from 0.1 to 5 mg/kg, preferably from 0.3 to 0.5 mg/kg, of body weight in order to achieve effective results while, in the case of intravenous administration, the daily dose is generally from about 0.01 to 100 mg/kg, preferably from 0.05 to 10 mg/kg, of body weight. The daily dose may be subdivided into several, for example 2, 3 or 4, subdoses, particularly when relatively large quantities are being administered. Where appropriate, it may be necessary, depending on the individual response, to diverge from the specified daily dose either in an upward or a downward direction.
Another embodiment of the instant invention includes an in vitro method of inhibiting the activation of vitronectin receptor in viable cells by delivering to these cells the compound of formula I, so that the compound competes with natural vitronectin ligand for binding but does not induce a biological response. Parameters and techniques for in vitro inhibition of cell receptors are known to those of skill in the art.